Inhibition of Cyclin-Dependent Kinase 1 by Purines and Pyrrolo[2,3-d]Pyrimidines Does Not Correlate with Antiviral Activity

We have previously shown that a series of nonnucleoside pyrrolo[2,3-d]pyrimidines selectively inhibit the replication of herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV). These compounds act at the immediate-early or early stage of HCMV replication and have antiviral properties somewhat similar to those of roscovitine and olomoucine, specific inhibitors of cyclin-dependent kinases (cdks). In the present study we examine the hypothesis that pyrrolo[2,3-d]pyrimidines exert their antiviral effects by inhibition of cellular cdks. Much higher concentrations of a panel of pyrrolo[2,3-d]pyrimidine nucleoside analogs with antiviral activity were required to inhibit recombinant cdk1/cyclin B compared to the submicromolar concentrations required to inhibit HCMV and HSV-1 replication. 4,6-Diamino-5-cyano-7-(2-phenylethyl)pyrrolo[2,3-d]pyrimidine (compound 1369) was the best inhibitor of cdk1 and cyclin B, with a 50% inhibitory concentration (IC(50); 14 μM) similar to that of roscovitine; it was competitive with respect to ATP (K(i) = 14 μM). The potency of compound 1369 against cdk1 and cyclin B was similar to its cytotoxicity (IC(50)s, 32 to 100 μM) but not its antiviral efficacy (IC(50)s, 0.02 to 0.3 μM). Thus, our results indicated the null hypothesis. In contrast, roscovitine was only weakly active against HSV-1 (IC(50), 38 μM) and HCMV (IC(50), 40 μM). These values were similar to those derived by cytotoxicity and cell growth inhibition assays, thereby suggesting that roscovitine is not a selective antiviral. Therefore, we propose that inhibition of cdk1 and cyclin B is not responsible for selective antiviral activity and that pyrrolo[2,3-d]pyrimidines constitute novel pharmacophores which compete with ATP to inhibit cdk1 and cyclin B

What we talk about when we talk about seasonality – A transdisciplinary review

The role of seasonality is indisputable in climate and ecosystem dynamics. Seasonal temperature and precipitation variability are of vital importance for the availability of food, water, shelter, migration routes, and raw materials. Thus, understanding past climatic and environmental changes at seasonal scale is equally important for unearthing the history and for predicting the future of human societies under global warming scenarios. Alas, in palaeoenvironmental research, the term ‘seasonality change’ is often used liberally without scrutiny or explanation as to which seasonal parameter has changed and how. Here we provide fundamentals of climate seasonality and break it down into external (insolation changes) and internal (atmospheric CO2 concentration) forcing, and regional and local and modulating factors (continentality, altitude, large-scale atmospheric circulation patterns). Further, we present a brief overview of the archives with potentially annual/seasonal resolution (historical and instrumental records, marine invertebrate growth increments, stalagmites, tree rings, lake sediments, permafrost, cave ice, and ice cores) and discuss archive-specific challenges and opportunities, and how these limit or foster the use of specific archives in archaeological research. Next, we address the need for adequate data-quality checks, involving both archive-specific nature (e.g., limited sampling resolution or seasonal sampling bias) and analytical uncertainties. To this end, we present a broad spectrum of carefully selected statistical methods which can be applied to analyze annually- and seasonally-resolved time series. We close the manuscript by proposing a framework for transparent communication of seasonality-related research across different communities